Obesity affects 1/3 of adults, is a major contributor to type 2 diabetes, cardiovascular disease and other several cancers, and is the second leading cause of preventable death in the United States. Effective anti-obesity drugs are urgently needed as behavior therapy offers limited success and bariatric surgery, while effective, has serious adverse consequences. Support for basic science research has led to the discovery of a number of new chemical signals and their receptors that contribute to energy balance control. Those discoveries have driven the development of new drugs. It is clear however, that energy balance control is multi-determined, with multiple signals, receptors, and regions of the brain operating with some degree of redundancy to insure that adequate energy is available for survival and reproduction. For this reason, it is important to be skeptical about whether emerging treatments will be efficacious in treating obesity. We argue that greater progress in developing effective anti-obesity drug therapies will result from research aimed at identifying the neurons and the neural circuits that are common to mediating the food intake inhibitory effects of different physiological signals, such as the adipose tissue-derived hormone leptin and gastrointestinal (GI) satiation signals. Our recent work shows that medial, nucleus solitarious (mNTS) leptin signaling amplifies the food intake inhibitory effects of various GI satiation signals. Complementing these results are data showing that targeted reduction in endogenous mNTS leptin receptor (LepRb) signaling (RNA interference [RNA-i]-mediated) triggers hyperphagia and weight gain, in part, via reduction in the food intake suppressive effect of GI satiation signals. These data establish that mNTS leptin signaling is physiologically relevant to the control of food intake and body weight. Recent pilot data complement these findings by showing that increased mNTS leptin signaling reduces the rewarding value of food and suppresses learned motivated behaviors directed towards food procurement. Aim I experiments use double immunohistochemistry to address whether mNTS LepRb+ neurons directly project to midbrain/forebrain nuclei associated with food intake control and assess the functional contributions of these projections to nucleus accumbens by measuring neural activity and dopamine release triggered by cues- associated with food reward and to the lateral hypothalamus by assessing intake behavioral and food reward effects of mNTS leptin. Aim II experiments employ behavioral, pharmacological, and genetic (RNA-i) strategies and neurophysiological experiments targeting LepRbEYFP neurons to determine whether descending hypothalamic oxytocin (OT) and orexin (ORX) projections to mNTS influence food intake by amplifying (ORX) or attenuating (OT) the mNTS processing of GI signals, LepRb signals or their combination. A variety of preliminary results support the hypotheses under investigation.